The long range objective of this research proposal is to study the hepatic process of gluconeogenesis from amino acids in vivo, that is, in the dog and ultimately in intact man. Specifically, we wish to accomplish the following: 1) to determine the contribution of circulating alanine to hepatic glucose production in the fed, postabsorptive, and prolonged-fasted states; 2) to define the physiological roles of insulin and glucagon in the regulation of gluconeogenesis from alanine; and 3) to study the pathophysiology of the accelerated gluconeogenesis of diabetic man. To accomplish these objectives, we will use the hepatic vein-brachial artery catheterization technique combined with a constant infusion of a radioactively-labeled amino acid, alanine-C14. Such a technique allows us to isolate the splanchnic bed in vivo and to measure the splanchnic alanine uptake and conversion to glucose and the contribution of circulating alanine to net hepatic glucose production. The roles of glucagon and insulin in regulating these parameters of gluconeogenesis can then be studied. These techniques will be used in 3 types of experiments. First, human subjects will be studied exactly as described above. Second, dogs will be studied utilizing the canine pancreatic autograft technique (2/3 pancreatectomy with exteriorization of the pancreatic remnant). This will produce a model of chronic pancreatic glucagon deficiency in which the physiological role of glucagon in regulating gluconeogenesis can be evaluated. Removal of the pancreatic remnant produces an animal devoid of both pancreatic insulin and glucagon, thus providing an ideal model in which to determine the "pure" effects of insulin and glucagon on gluconeogenesis. Third, dogs will also be studied utilizing somatostatin, a hypothalamic hormone, known to suppress glucagon and insulin secretion. This technique will provide us with an in vivo model of acute glucagon and insulin deficiency, in which the regulatory roles of these two hormones on gluconeogenesis can also be studied. Extension to man of such studies utilizing somatostatin is planned. These studies will provide insight into the quantitative role of gluconeogenesis from amino acids as a source of hepatic glucose production and help define the regulatory roles of insulin and glucagon in controlling gluconeogenesis in vivo.